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A lysosome-centered view of nutrient homeostasis.

Mony VK, Benjamin S, O'Rourke EJ - Autophagy (2016)

Bottom Line: Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane.However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks.Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake.

View Article: PubMed Central - PubMed

Affiliation: a Department of Biology , College of Arts and Sciences, University of Virginia , Charlottesville , VA , USA.

ABSTRACT
Lysosomes are highly acidic cellular organelles traditionally viewed as sacs of enzymes involved in digesting extracellular or intracellular macromolecules for the regeneration of basic building blocks, cellular housekeeping, or pathogen degradation. Bound by a single lipid bilayer, lysosomes receive their substrates by fusing with endosomes or autophagosomes, or through specialized translocation mechanisms such as chaperone-mediated autophagy or microautophagy. Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane. However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks. The lysosome is emerging as a signaling hub that can integrate and relay external and internal nutritional information to promote cellular and organismal homeostasis, as well as a major contributor to the processing of energy-dense molecules like glycogen and triglycerides. Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake. At the same time, we highlight the value of genomics approaches to the past and future discoveries of how the lysosome simultaneously executes and controls cellular homeostasis.

No MeSH data available.


Related in: MedlinePlus

The lysosome is a nutrient-sensing center. When nutrients are sufficient (upper panel), amino acids induce structural changes in the lysosomal vacuolar-type ATPase (V-ATPase), so that it weakens its association with the Ragulator-RAG complex. Thus, Ragulator-RAG can recruit MTOR to the lysosomal membrane.23 The small GTPase RHEB that resides at the lysosomal membrane, can now stimulate the phosphorylation and consequent activation of MTOR.28,29 RRAGA/B facilitates MTOR activation and recruitment of TFEB to the lysosome for its phosphorylation and retention in the cytoplasm by YWHA chaperones.9,26,47 When nutrients are scarce (bottom panel), the RAG GTPases recruit TSC (tuberous sclerosis complex), which converts GTP-RHEB to GDP-RHEB causing inactivation and release of MTOR into the cytosol.27 Fasting stimulates AMPK, which in turn activates the TSC complex. In addition, since MTOR phosphorylates the MiTs transcription factors, upon MTOR inhibition, these transcriptional regulators are not phosphorylated and are free to translocate to the nucleus and activate genes involved in lysosomal biogenesis and function.46,48,50,51
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f0001: The lysosome is a nutrient-sensing center. When nutrients are sufficient (upper panel), amino acids induce structural changes in the lysosomal vacuolar-type ATPase (V-ATPase), so that it weakens its association with the Ragulator-RAG complex. Thus, Ragulator-RAG can recruit MTOR to the lysosomal membrane.23 The small GTPase RHEB that resides at the lysosomal membrane, can now stimulate the phosphorylation and consequent activation of MTOR.28,29 RRAGA/B facilitates MTOR activation and recruitment of TFEB to the lysosome for its phosphorylation and retention in the cytoplasm by YWHA chaperones.9,26,47 When nutrients are scarce (bottom panel), the RAG GTPases recruit TSC (tuberous sclerosis complex), which converts GTP-RHEB to GDP-RHEB causing inactivation and release of MTOR into the cytosol.27 Fasting stimulates AMPK, which in turn activates the TSC complex. In addition, since MTOR phosphorylates the MiTs transcription factors, upon MTOR inhibition, these transcriptional regulators are not phosphorylated and are free to translocate to the nucleus and activate genes involved in lysosomal biogenesis and function.46,48,50,51

Mentions: Although how nutrient sufficiency leads to recruitment of MTORC1 to the lysosomal surface is not fully understood, lysosomal localization and interaction with its activator RHEB are required for full MTOR activation. The small GTPase RHEB (Ras homolog enriched in brain), stimulates the phosphorylation and activation of MTORC1 when bound to GTP in a nutrient-abundant state. Upon amino acid withdrawal or the inhibition of growth factor signaling, RAG GTPases recruit TSC (tuberous sclerosis complex) to the lysosomes.27 TSC, which acts as a GTPase-activating protein for RHEB, is composed of TSC1, TSC2, and the GTPase TBC1D7, which converts GTP-RHEB to GDP-RHEB preventing its stimulatory effect on MTORC1 (Fig. 1).28,29 The GTP/GDP-independent activation of MTORC1 by RHEB may implicate other modulators in RHEB-mediated activation of MTORC1.30Figure 1.


A lysosome-centered view of nutrient homeostasis.

Mony VK, Benjamin S, O'Rourke EJ - Autophagy (2016)

The lysosome is a nutrient-sensing center. When nutrients are sufficient (upper panel), amino acids induce structural changes in the lysosomal vacuolar-type ATPase (V-ATPase), so that it weakens its association with the Ragulator-RAG complex. Thus, Ragulator-RAG can recruit MTOR to the lysosomal membrane.23 The small GTPase RHEB that resides at the lysosomal membrane, can now stimulate the phosphorylation and consequent activation of MTOR.28,29 RRAGA/B facilitates MTOR activation and recruitment of TFEB to the lysosome for its phosphorylation and retention in the cytoplasm by YWHA chaperones.9,26,47 When nutrients are scarce (bottom panel), the RAG GTPases recruit TSC (tuberous sclerosis complex), which converts GTP-RHEB to GDP-RHEB causing inactivation and release of MTOR into the cytosol.27 Fasting stimulates AMPK, which in turn activates the TSC complex. In addition, since MTOR phosphorylates the MiTs transcription factors, upon MTOR inhibition, these transcriptional regulators are not phosphorylated and are free to translocate to the nucleus and activate genes involved in lysosomal biogenesis and function.46,48,50,51
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836021&req=5

f0001: The lysosome is a nutrient-sensing center. When nutrients are sufficient (upper panel), amino acids induce structural changes in the lysosomal vacuolar-type ATPase (V-ATPase), so that it weakens its association with the Ragulator-RAG complex. Thus, Ragulator-RAG can recruit MTOR to the lysosomal membrane.23 The small GTPase RHEB that resides at the lysosomal membrane, can now stimulate the phosphorylation and consequent activation of MTOR.28,29 RRAGA/B facilitates MTOR activation and recruitment of TFEB to the lysosome for its phosphorylation and retention in the cytoplasm by YWHA chaperones.9,26,47 When nutrients are scarce (bottom panel), the RAG GTPases recruit TSC (tuberous sclerosis complex), which converts GTP-RHEB to GDP-RHEB causing inactivation and release of MTOR into the cytosol.27 Fasting stimulates AMPK, which in turn activates the TSC complex. In addition, since MTOR phosphorylates the MiTs transcription factors, upon MTOR inhibition, these transcriptional regulators are not phosphorylated and are free to translocate to the nucleus and activate genes involved in lysosomal biogenesis and function.46,48,50,51
Mentions: Although how nutrient sufficiency leads to recruitment of MTORC1 to the lysosomal surface is not fully understood, lysosomal localization and interaction with its activator RHEB are required for full MTOR activation. The small GTPase RHEB (Ras homolog enriched in brain), stimulates the phosphorylation and activation of MTORC1 when bound to GTP in a nutrient-abundant state. Upon amino acid withdrawal or the inhibition of growth factor signaling, RAG GTPases recruit TSC (tuberous sclerosis complex) to the lysosomes.27 TSC, which acts as a GTPase-activating protein for RHEB, is composed of TSC1, TSC2, and the GTPase TBC1D7, which converts GTP-RHEB to GDP-RHEB preventing its stimulatory effect on MTORC1 (Fig. 1).28,29 The GTP/GDP-independent activation of MTORC1 by RHEB may implicate other modulators in RHEB-mediated activation of MTORC1.30Figure 1.

Bottom Line: Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane.However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks.Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake.

View Article: PubMed Central - PubMed

Affiliation: a Department of Biology , College of Arts and Sciences, University of Virginia , Charlottesville , VA , USA.

ABSTRACT
Lysosomes are highly acidic cellular organelles traditionally viewed as sacs of enzymes involved in digesting extracellular or intracellular macromolecules for the regeneration of basic building blocks, cellular housekeeping, or pathogen degradation. Bound by a single lipid bilayer, lysosomes receive their substrates by fusing with endosomes or autophagosomes, or through specialized translocation mechanisms such as chaperone-mediated autophagy or microautophagy. Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane. However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks. The lysosome is emerging as a signaling hub that can integrate and relay external and internal nutritional information to promote cellular and organismal homeostasis, as well as a major contributor to the processing of energy-dense molecules like glycogen and triglycerides. Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake. At the same time, we highlight the value of genomics approaches to the past and future discoveries of how the lysosome simultaneously executes and controls cellular homeostasis.

No MeSH data available.


Related in: MedlinePlus